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Cytotoxic T cells isolated from healthy donors and cancer patients kill TGFβ-expressing cancer cells in a TGFβ-dependent manner.

ABSTRACT: Transforming growth factor-beta (TGFβ) is a highly potent immunosuppressive cytokine. Although TGFβ is a tumor suppressor in early/premalignant cancer lesions, the cytokine has several tumor-promoting effects in advanced cancer; abrogation of the antitumor immune response is one of the most important tumor-promoting effects. As several immunoregulatory mechanisms have recently been shown to be targets of specific T cells, we hypothesized that TGFβ is targeted by naturally occurring specific T cells and thus could be a potential target for immunomodulatory cancer vaccination. Hence, we tested healthy donor and cancer patient T cells for spontaneous T-cell responses specifically targeting 38 20-mer epitopes derived from TGFβ1. We identified numerous CD4⁺ and CD8⁺ T-cell responses against several epitopes in TGFβ. Additionally, several ex vivo responses were identified. By enriching specific T cells from different donors, we produced highly specific cultures specific to several TGFβ-derived epitopes. Cytotoxic CD8⁺ T-cell clones specific for both a 20-mer epitope and a 9-mer HLA-A2 restricted killed epitope peptide were pulsed in HLA-A2⁺ target cells and killed the HLA-A2⁺ cancer cell lines THP-1 and UKE-1. Additionally, stimulation of THP-1 cancer cells with cytokines that increased TGFβ expression increased the fraction of killed cells. In conclusion, we have shown that healthy donors and cancer patients harbor CD4⁺ and CD8⁺ T cells specific for TGFβ-derived epitopes and that cytotoxic T cells with specificity toward TGFβ-derived epitopes are able to recognize and kill cancer cell lines in a TGFβ-dependent manner.

SUBMITTER: Holmstrom MO

PROVIDER: S-EPMC8027197 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Engineered FVIII-expressing cytotoxic T cells target and kill FVIII-specific B cells in vitro and in vivo.

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A Genetically Modified attenuated <i>Listeria</i> Vaccine Expressing HPV16 E7 Kill Tumor Cells in Direct and Antigen-Specific Manner.

Project description:Attenuated Listeria monocytogenes (L. monocytogenes, LM) induces specific CD8+ and CD4+ T cell responses, and has been identified as a promising cancer vaccine vector. Cervical cancer is the third most common cancer in women worldwide, with human papillomavirus (HPV), particularly type 16, being the main etiological factor. The therapeutic HPV vaccines are urgently needed. The E7 protein of HPV is necessary for maintaining malignancy in tumor cells. Here, a genetically modified attenuated LM expressing HPV16 E7 protein was constructed. Intraperitoneal vaccination of LM4Δhly::E7 significantly reduced tumor size and even resulted in complete regression of established tumors in a murine model of cervical cancer. We provided evidence that recombinant LM strains could enter the tumor tissue and induce non-specific tumor cell death, probably via activation of reactive oxygen species and increased intracellular Ca2+ levels. LM4Δhly::E7 effectively triggered a strong antigen-specific cellular immunity in tumor-bearing mice, and elicited significant infiltration of T cells in the intratumoral milieu. In summary, these data showed LM4Δhly::E7 to be effective in a cervical cancer model and LM4Δhly::E7 induced an antitumor effect by antigen-specific cellular immune responses and direct killing of tumor cells, indicating a potential application against cervical cancer.

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